In recent years, oil-in-water type emulsions, in particularly such in which the droplets are of a submicron size (hereinafter "submicron emulsions") gained increasing importance as vehicles for delivery of hydrophobic drugs. Formulations of submicron emulsions reported in the literature to date were usually based on a combination of lecithins which are mixtures of phospholipids of various compositions obtained from natural sources, non-ionic or ionic surfactants and of oil such as vegetable oil. Lecithins generally comprise phosphatidylcholine as the major component, which is a zwitterion that is neutral over a wide pH range, and negatively charged phospholipids such as phosphatidylethanolamine, phosphatidylserine and phosphatidic acid. As a consequence of their composition, the colloid particles in all emulsions available to date were negatively charged.
In order to increase stability of emulsions it was generally accepted that the charge of the colloid particles, or the so called "zeta potential", should be made as negative as possible, e.g. by the addition of various non-ionic or also negatively charged surfactants. However, negatively charged particles have a tendency of absorption of cations such as sodium and calcium ions which are present in all physiological fluids. Such absorption decreases the net surface charge of the particles and may eventually cause the breakdown of the droplets and the coalesence of small droplets to form larger ones. For the long term stability of such emulsions it was always necessary to prepare them with deionized water. A further problem of such emulsions resides in that the surface of biological membranes is generally negatively charged and there is thus an electrostatic repulsion between such membranes and the negatively charged colloid particles of the emulsion. This is at times a serious drawback for various applications.
Thus, against the very high potential of emulsions, and in particularly submicron emulsions, as drug delivery of vehicles, there are the above noted drawbacks.
European Patent Application 372331 discloses oil-in-water type emulsions, for parenteral administration which contain phospholipids as emulsifiers and being characterized in that they comprise physiologically acceptable concentrations of non-toxic divalent or trivalent metal cations so that the zeta potential is in the range of (+)8-20 millivolts. As disclosed in this patent application, the emulsions are not destabilized by the addition of electrolytes and are useful for making a total nutrient, electrolyte-containing parenteral feeding systems. These nutritional emulsions, however, are not suitable as drug delivery systems of hydrophobic drugs since they are sensitive to the incorporation of drugs to their inner oil phase which causes a phase separation. Furthermore, upon introduction of the emulsions into a physiological fluid, introduction of the emulsions into a physiological fluid, e.g. blood, the concentration of the divalent and the trivalent cations immediately decreases as a result dilution and of the very strong buffering potential of physiological fluids and accordingly the particles are likely to break down. Such breakdown may be of little consequence where the emulsion is used for the purpose of nutrition but it renders such emulsions unsuitable for use as drug delivery vehicles.
It is an object of the present invention to provide novel oil-in-water type emulsions useful as drug delivery vehicles which overcome some of the above noted drawbacks of the prior art.
It is a further object of the present invention to provide novel oil-in-water type emulsions wherein the colloid particles are positively charged as a result of the combined properties of the surface active substances, i.e. without the need to add cations.